Inflammatory Lung Lesions Research Articles

A case of necrotic pneumonia caused by Streptococcus pneumoniae was diagnosed using a pneumonia antigen test in BALF: A case report.

Streptococcus pneumoniae is a common cause of community-acquired pneumonia. Currently, it is believed that many cases of pulmonary infection with negative results on pathogenic testing are caused by S. pneumoniae. There have been no reports of the detection of S. pneumoniae antigen in lung lavage fluid. An elderly male patient with suboptimal fasting blood glucose control and a history of liver abscess. Chest computed tomography (CT) revealed inflammatory lesions in both lungs with consolidation in the middle lobe of the right lung. After admission, we collected alveolar lavage fluid in a timely manner and performed pneumococcal antigen detection and etiological testing. Prompt testing for pneumococcal antigen in bronchoalveolar lavage fluid yielded a positive clinical outcome. Subsequent analysis via bacterial culture of sputum and next-generation sequencing (mNGS) of BALF definitively identified S. pneumoniae as the etiological agent. Following the analysis of drug sensitivity test results from the identified pathogens, adjustments were made to the antibiotic regimen, and appropriate pus puncture drainage was performed. Subsequently, the patient's condition improved, leading to discharge. The identification of S. pneumoniae antigen in bronchoalveolar lavage fluid may facilitate earlier and more precise diagnosis of pneumonia attributed to S. pneumoniae.

Enhanced study design for acute inhalation studies with hydrophobic surface-treated particles to determine toxicological effects including suffocation

High concentrations of low-density particles may cause effects in acute inhalation toxicity studies which can be easily underestimated or misinterpreted following strictly the OECD TG 436, i.e., limited parameters as mortality and gross lesions will be evaluated only. Seven particle types (synthetic amorphous silica (SAS) HMDZ-SAS, silica gel, pyrogenic SAS, and precipitated SAS, calcium carbonate, aluminum oxide pyrogenic alumina, organic red pigment) were chosen at the highest technically feasible concentration of approximately 500 mg/m3 for acute inhalation studies with an expanded endpoint setup. Therefore additional parameters and a thorough histopathological evaluation of an extensive set of organs, including the respiratory tract emphasizing the nasal cavities were added. Six Crl:WI rats per study were exposed for four hours from which three animals were sacrificed after 24 hours and three animals after 14 days. HMDZ-SAS caused early death in all animals due to blockage of the nasal passages caused by its hydrophobicity. For all other Si-containing compounds, histology revealed minor inflammatory and reactive lesions in lungs after 24 hours that were still present after 14 days, except in silica gel-treated animals. After 14 days, for pyrogenic SAS, precipitated SAS, and pyrogenic alumina, granulomas formed in the BALT and lung-associated lymph nodes. In contrast, the calcium carbonate induced almost no findings, and the red pigment (also tested for the additional dose of 1000 mg/m3) stuck partially to the nasal mucosa without causing pathological damage and partly entered the lungs without showing any adverse effects. The results of the present study highlight the advantage of improving the rather simple study design of acute inhalation studies by implementing an extended study design.

Value of [18F]AlF-NOTA-FAPI-04 PET/CT for differential diagnosis of malignant and various inflammatory lung lesions: comparison with [18F]FDG PET/CT.

Uptake of the imaging tracers [18F]AlF-NOTA-FAPI-04 and [18F]FDG varies in some inflammatory lesions, which may result in false-positive findings for malignancy on PET/CT. Our aim was to compare the [18F]AlF-NOTA-FAPI-04 and [18F]FDG PET/CT imaging features of malignant and various inflammatory lung lesions and to analyze their value for differential diagnosis. We retrospectively analyzed [18F]AlF-NOTA-FAPI-04 PET/CT scans from 67 cancer patients taken between December 2020 and January 2022, as well as the scans of 32 patients who also underwent [18F]FDG PET/CT imaging. The maximum and mean standardized uptake values (SUVmax and SUVmean, respectively) and lesion-to-background ratio (LBR) were calculated. The predictive capabilities of semiquantitative PET/CT parameters were analyzed by receiver operating characteristic curve analysis. A total of 70 inflammatory and 37 malignant lung lesions were evaluated by [18F]AlF‑NOTA‑FAPI‑04 PET/CT, and 33 inflammatory and 26 malignant lung lesions also were evaluated by [18F]FDG PET/CT. Inflammatory lesions exhibited lower [18F]AlF-NOTA-FAPI-04 and [18F]FDG uptake compared to malignant lesions, with statistically significant differences in SUVmax, SUVmean, and LBR (all p < 0.001). [18F]AlF-NOTA-FAPI-04 uptake also varied among different types of inflammatory lesions (SUVmax, p = 0.005; SUVmean, p = 0.008; LBR, p < 0.001), with the highest uptake observed in bronchiectasis with infection, followed by postobstructive pneumonia, and the lowest in pneumonia. [18F]FDG uptake was higher in postobstructive pneumonia than in pneumonia (SUVmax, p = 0.009; SUVmean, p = 0.016; LBR, p = 0.004). [18F]AlF-NOTA-FAPI-04/[18F]FDG PET/CT showed significantly lower uptake in inflammatory lesions than malignancies as well as variation in different types of inflammatory lesions, and thus, may be valuable for distinguishing malignant and various inflammatory findings. Our study confirmed that the uptake of [18F]AlF-NOTA-FAPI-04/[18F]FDG PET/CT in inflammatory and malignant lung lesions is different, which is beneficial to distinguish inflammatory and malignant lung lesions in clinic. • Malignant and different inflammatory lung lesions showed varying degrees of uptake of [18F]AlF-NOTA-FAPI-04 and [18F]FDG. • Inflammatory lung lesions showed significantly less uptake than malignancies, and uptake varied among different types of inflammatory lesions. • Both types of PET/CT could differentiate malignant and various inflammatory lung findings.

Interorgan communication networks in the kidney-lung axis.

The homeostasis and health of an organism depend on the coordinated interaction of specialized organs, which is regulated by interorgan communication networks of circulating soluble molecules and neuronal connections. Many diseases that seemingly affect one primary organ are really multiorgan diseases, with substantial secondary remote organ complications that underlie a large part of their morbidity and mortality. Acute kidney injury (AKI) frequently occurs in critically ill patients with multiorgan failure and is associated with high mortality, particularly when it occurs together with respiratory failure. Inflammatory lung lesions in patients with kidney failure that could be distinguished from pulmonary oedema due to volume overload were first reported in the 1930s, but have been largely overlooked in clinical settings. A series of studies over the past two decades have elucidated acute and chronic kidney-lung and lung-kidney interorgan communication networks involving various circulating inflammatory cytokines and chemokines, metabolites, uraemic toxins, immune cells and neuro-immune pathways. Further investigations are warranted to understand these clinical entities of high morbidity and mortality, and to develop effective treatments.

Microenvironmental Changes in Mediastinal Fat-associated Lymphoid Clusters and Lungs in Early and Late Stages of Metastatic Lung Cancer Induction.

The prognosis of metastatic lung melanoma (MLM) has been reported to be poor. An increasing number of studies have reported the function of several immune cells in cancer regression. Although the function of mediastinal fat-associated lymphoid clusters (MFALCs) in the progression of inflammatory lung lesions has been previously reported, the association between MLM progression and MFALCs development has remained unexplored. Herein, we compared the microenvironmental changes in the lungs and MFALCs among phosphate-buffered saline (PBS) and cancer groups at early (1 week) and late (2 weeks) stages following the intravenous injection of B16-F10 melanoma cells into C57BL/6 mice. Except for lung CD4+ helper T-cells and Iba1+ macrophage populations of early stage, we observed a significant increase in the proliferating and immune cell (CD20+ B-lymphocytes, CD3+ T-lymphocytes, CD8+ cytotoxic T-cells, CD16+ natural killer (NK) cells populations, area of high endothelial venules, and lung lymphatic vessels in cancer groups at both the stages as compared with the PBS groups. Furthermore, a significant positive correlation was observed between immune cell populations in MFALCs and the lungs (B- and T-lymphocytes, and NK cells in both stages). Collectively, our findings suggest a promising cancer therapeutic strategy via targeting immune cells in MFALCs.

Risk of bloodstream infections in allogeneic hematopoietic cell transplant recipients according to gut mucosal colonization and fluoroquinolone implementation during neutropenia

Background . Higher rate of gram-negative bloodstream infections (BSI) have been recently documented from transplantation centers providing fluoroquinolone (FQ) prophylaxis. Aim . To define the incidence of BSI during neutropenia according to gut mucosal colonization with resistant gramnegative bacteria and FQ administration. Materials and methods . Of 284 allogeneic hematopoietic cell transplant recipients included in the study, 154 (54.2 %) were identified as colonized with resistant gram-negative bacteria, and 130 (45.8 %) patients as non-colonized. Resistant gram-negative bacteria included Enterobacterales with extended spectrum beta-lactamase production, carbapenem-resistant Enterobacterales, Stenotrophomonas maltophilia , and carbapenem-resistant strains of Pseudomonas aeruginosa . Colonized patients did not receive FQ prophylaxis (n = 147) except 7 patients who received FQ as sequential therapy due to residual inflammatory lung lesions. Among non-colonized patients 98 received FQ prophylaxis, whereas 32 did not. Results . Probability of gram-negative BSI (71.4 %; p &lt;0.0001), and extended spectrum beta-lactamase-producing Enterobacterales BSI (57.1 %; p &lt;0.0001) was significantly higher in colonized patients receiving FQ. No significant difference was found in probability of gram-positive BSI (p = 0.452). In multivariate analysis colonized patients with (hazard ratio (HR) 35.32; 95 % confidence interval (CI) 9.15–136.44; p &lt;0.0001) or without FQ (HR 3.44; 95 % CI 1.15–10.31; p = 0.007), omission of FQ in non-colonized patients (HR 4.03; 95 % CI 1.08–15.00; p = 0.038), and active disease before allogeneic hematopoietic cell transplantation (HR 2.17; 95 % CI 1.03–4.63; p = 0.042) were associated with higher risk of gram-negative BSI, whereas mismatched unrelated donor transplantations were associated with higher gram-positive BSI risk (HR 3.84; 95 % CI 1.63–9.08; p = 0,009). Conclusion . Colonization with multiresistant gram-negative bacteria is a predictor of gram-negative BSI, including multiresistant pathogens, especially when FQ are prescribed during neutropenia, while in non-colonized patients FQ prophylaxis is an effective approach significantly reducing gram-negative BSI.

A Combined Approach for Detection of Ovine Small Ruminant Retrovirus Co-Infections.

Jaagsiekte retrovirus (JSRV)-induced ovine pulmonary adenocarcinoma (OPA) is an important ovine respiratory disease in Switzerland. Furthermore, ovine lungs with OPA frequently exhibited lesions suggestive of maedi-visna virus (MVV) or caprine arthritis encephalitis virus (CAEV) infection, indicating that co-morbidities might occur. Lungs and pulmonary lymph nodes were sampled from suspected OPA cases, inflammatory lung lesions and control lungs (total of 110 cases). Tissues were (a) processed for histology and immunohistochemistry (IHC), and (b) underwent DNA extraction and real-time PCR for JSRV, MVV and CAEV. Peptide sequences were used to generate virus-specific customized polyclonal antibodies. PCR-positive OPA cases and formalin-fixed and paraffin-embedded MVV- and CAEV-infected synovial cell pellets served as positive controls. Fifty-two lungs were histologically diagnosed with OPA. Histological evidence of MVV/CAEV infection was detected in 25 lungs. JSRV was detected by PCR in 84% of the suspected OPA cases; six were co-infected with MVV and one with CAEV. MVV was detected by PCR in 14 cases, and four lungs were positive for CAEV. Three lungs had MVV/CAEV co-infection. In IHC, JSRV was detected in 91% of the PCR-positive cases, whereas MVV and CAEV immunoreactivity was seen in all PCR-positive lungs. Although PCR showed a higher sensitivity compared to IHC, the combined approach allows for investigations on viral cell tropism and pathogenic processes in co-morbidities, including their potential interdependency. Furthermore, an immunohistochemical tool for specific differentiation of MVV and/or CAEV infection was implemented.

Cold-adapted SARS-CoV-2 variants with different temperature sensitivity exhibit an attenuated phenotype and confer protective immunity.

As novel SARS-CoV-2 Variants of Concern emerge, the efficacy of existing vaccines against COVID-19 is declining. A possible solution to this problem lies in the development of a live attenuated vaccine potentially able of providing cross-protective activity against a wide range of SARS-CoV-2 antigenic variants. Cold-adapted (ca) SARS-CoV-2 variants, Dubrovka-ca-B4 (D-B4) and Dubrovka-ca-D2 (D-D2), were obtained after long-term passaging of the Dubrovka (D) strain in Vero cells at reduced temperatures. Virulence, immunogenicity, and protective activity of SARS-CoV-2 variants were evaluated in experiments on intranasal infection of Syrian golden hamsters (Mesocricetus auratus). In animal model infecting with ca variants, the absence of body weight loss, the significantly lower viral titer and viral RNA concentration in animal tissues, the less pronounced inflammatory lesions in animal lungs as compared with the D strain indicated the reduced virulence of the virus variant. Single intranasal immunization with D-B4 and D-D2 variants induced the production of neutralizing antibodies in hamsters and protected them from infection with the D strain and the development of severe pneumonia. It was shown that for ca SARS-CoV-2 variants, the temperature-sensitive (ts) phenotype was not obligate for virulence reduction. Indeed, the D-B4 variant, which did not possess the ts phenotype but had lost the ability to infect human lung cells Calu-3, exhibited reduced virulence in hamsters. Consequently, the potential phenotypic markers of attenuation of ca SARS-CoV-2 variants are the ca phenotype, the ts phenotype, and the change in species specificity of the virus. This study demonstrates the great potential of SARS-CoV-2 cold adaptation as a strategy to develop a live attenuated COVID-19 vaccine.

Autoreactive napsin A-specific T cells are enriched in lung tumors and inflammatory lung lesions during immune checkpoint blockade.

Cancer treatment with immune checkpoint blockade (ICB) often induces immune-related adverse events (irAEs). We hypothesized that proteins coexpressed in tumors and normal cells could be antigenic targets in irAEs and herein described DITAS (discovery of tumor-associated self-antigens) for their identification. DITAS computed transcriptional similarity between lung tumors and healthy lung tissue based on single-sample gene set enrichment analysis. This identified 10 lung tissue-specific genes highly expressed in the lung tumors. Computational analysis was combined with functional T cell assays and single-cell RNA sequencing of the antigen-specific T cells to validate the lung tumor self-antigens. In patients with non-small cell lung cancer (NSCLC) treated with ICB, napsin A was a self-antigen that elicited strong CD8+ T cell responses, with ICB responders harboring higher frequencies of these CD8+ T cells compared with nonresponders. Human leukocyte antigen (HLA) class I ligands derived from napsin A were present in human lung tumors and in nontumor lung tissues, and napsin A tetramers confirmed the presence of napsin A-specific CD8+ T cells in blood and tumors of patients with NSCLC. Napsin A-specific T cell clonotypes were enriched in lung tumors and ICB-induced inflammatory lung lesions and could kill immortalized HLA-matched NSCLC cells ex vivo. Single-cell RNA sequencing revealed that these T cell clonotypes expressed proinflammatory cytokines and cytotoxic markers. Thus, DITAS successfully identified self-antigens, including napsin A, that likely mediate effective antitumor T cell responses in NSCLC and may simultaneously underpin lung irAEs.

Total Severity Score (TSS) comparison in vaccinated and unvaccinated patients during the fourth wave (December 2021 - January 2022) of COVID-19 in Italy.

This study aims at comparing the severity score assessed using high-resolution computed tomography (HRCT) in vaccinated and unvaccinated COVID-19 patients. From the first of December 2021 to first of February 2022, we conducted a single-center retrospective analysis on COVID-19 patients who accessed ED services. The hospital in question is a level II facility with a catchment area of around 200,000 people. According to the Italian recommendations, patients were divided into four groups based on the CT score of Micheal Chung. The sum of acute inflammatory lung lesions involving each lobe was scored as 1 (0-25%), 2 (26-50%), 3 (51-75%) or 4 (76-100%) on a visual quantitative assessment of CT. The total severity score (TSS) was determined by summing the five lobe scores. The study included 134 patients divided into two groups: 67 vaccinated and 67 unvaccinated people. 53 people had incomplete (single dose/double dose) immunization, while 14 people completed the vaccination cycle. It was discovered that the mean CT severity score was lower in fully vaccinated patients compared to partially vaccinated or unvaccinated patients. The mean CT score was significantly lower in fully vaccinated patients aged 60 compared to older patients. The mean CT score was higher in unvaccinated patients compared to fully vaccinated patients. Individuals who received three doses of COVID-19 vaccination had lower CT severity scores than patients who received only one dose of vaccine or no vaccines at all.

Autoreactive napsin A-specific T cells are enriched in lung tumors and inflammatory lung lesions during checkpoint blockade

Autoreactive napsin A-specific T cells are enriched in lung tumors and inflammatory lung lesions during checkpoint blockade

Control of Foxp3+ Treg Production, Stability and Function by the Nuclear Co‐regulator, Sin3A

PurposeFoxp3+ T‐regulatory (Treg) cells are well established as a crucial component of immune homeostasis and self‐tolerance. Histone/protein deacetylase (HDAC) activity within Foxp3+ Tregs plays an important role in regulation of gene expression. HDAC1 and ‐2 regulate Foxp3 expression and play critical roles in the control of Treg functions and properties. Less understood, are the contributions made by proteins which form large complexes with HDAC1 and ‐2, such as the paired amphipathic helix protein, Sin3a.MethodsWe sought to evaluate the contributions Sin3a makes to Tregs by undertaking its conditional deletion in Foxp3+ cells.ResultsSin3a‐/‐Foxp3Cre mice developed severe, systemic autoimmunity, leading to death within 2‐3 weeks of birth. These mice had greatly enlarged superficial lymph nodes, massive inflammatory lesions in lungs, skin, livers and kidneys and developed autoantibodies to islet cells, striated muscles, keratin, endomysium and gastric parietal cells. Percentages of Foxp3+ Tregs in the secondary lymphoid organs of Sin3a‐/‐Foxp3Cre mice were vastly lower than in controls (p values ranging from &gt;0.01 to &gt;0.0001). Further, the amount of Foxp3 mRNA expression (&gt;20‐fold) and Foxp3 protein per Treg (&gt;3‐fold) were also significantly reduced within Sin3a deficient animals. The ratios of T effectors to Tregs, and follicular T effectors to follicular Tregs were drastically increased within the spleens and superficial lymph nodes (ranging from 87‐154% and 152‐160%, respectively). Sin3a deficient Tregs produced significant amounts of pro‐inflammatory cytokines, including Granzyme B, IFN‐γ and IL‐2 (ranging from 12‐45% of cells). Tregs lacking Sin3a had impaired suppressive function against CD4+ and CD8+ responders (p&lt;0.01 and p&lt;0.05 respectively, compared to WT Tregs) in vitro. In addition, we found that Sin3a was essential for peripheral iTreg conversion since conventional CD4+CD25‐ cells from Sin3a‐/‐FoxP3Cre mice completely lacked the ability to convert to Foxp3+ iTregs ex vivo in the presence of IL‐2, TGFb, and CD3/CD28 beads. Consistent with impaired Treg function, CD4+ and CD8+ T cells from Sin3a‐/‐Foxp3Cre mice showed increased activation ex vivo (Ki67+ and CD69+ increased 120% and 230%, respectively) and enhanced production of Granzyme B and cytokines IFN‐γ and IL‐2 upon stimulation in vitro. To gain a more complete understanding of the regulatory role of Sin3a in Tregs, we are in the process of performing RNAseq. To address the vast reduction of Foxp3+ Tregs within Sin3a‐/‐FoxP3Cre mice we are investigating methylation of the CNS2 intronic region of Foxp3 by bisulphite conversion and determining the fate of Tregs in vivo by lineage tracing.ConclusionsThese data show that the nuclear co‐regulator, Sin3a, functions in modulating Treg gene expression and helps maintain the unique properties of these key immune cells. Our results indicate a potential for therapeutic modulation of Treg functions by pharmacologic targeting of components within the Sin3a complex.

The Ameliorative Effect of Dexamethasone on the Development of Autoimmune Lung Injury and Mediastinal Fat-Associated Lymphoid Clusters in an Autoimmune Disease Mouse Model.

In our previous study, we revealed the ameliorative therapeutic effect of dexamethasone (Dex) for Lupus nephritis lesions in the MRL/MpJ-Fas lpr/lpr (Lpr) mouse model. The female Lpr mice developed a greater number of mediastinal fat-associated lymphoid clusters (MFALCs) and inflammatory lung lesions compared to the male mice. However, the effect of Dex, an immunosuppressive drug, on both lung lesions and the development of MFALCs in Lpr mice has not been identified yet. Therefore, in this study, we compared the development of lung lesions and MFALCs in female Lpr mice that received either saline (saline group “SG”) or dexamethasone (dexamethasone group “DG”) in drinking water as a daily dose along with weekly intraperitoneal injections for 10 weeks. Compared to the SG group, the DG group showed a significant reduction in the levels of serum anti-dsDNA antibodies, the size of MFALCs, the degree of lung injury, the area of high endothelial venules (HEVs), and the number of proliferating and immune cells in both MFALCs and the lungs. A significant positive correlation was observed between the size of MFALCs and the cellular aggregation in the lungs of Lpr mice. Therefore, this study confirmed the ameliorative effect of Dex on the development of lung injury and MFALCs via their regressive effect on both immune cells’ proliferative activity and the development of HEVs. Furthermore, the reprogramming of MFALCs by targeting immune cells and HEVs may provide a therapeutic strategy for autoimmune-disease-associated lung injury.

Caspase 9b Drives Cellular Transformation, Lung Inflammation, and Lung Tumorigenesis.

Our findings show that C9b can directly activate NF-κB pathway in vivo to modulate lung inflammation, immune cell influx, and peripheral immune responses, which demonstrates that C9b is key factor in driving cell transformation and lung tumorigenesis.

A patient with eosinophilic granulomatosis with polyangiitis successfully weaned from corticosteroids through remission induction therapy with mepolizumab

The patient was a 74-year-old man who was admitted to our hospital for fever, purpura, abdominal pain, and bilateral numbness. Although the patient tested negative for anti-neutrophil cytoplasmic antibody (ANCA), he presented with an elevated peripheral eosinophil count, increased inflammatory responses, duodenitis, cholecystitis, lung lesions, renal disorder, and peripheral neuropathy. The skin biopsy findings revealed vasculitis. Thus, the patient was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA). Given the advanced age of the patient, in addition to the poor general condition and hepatic and renal dysfunction, administration of immunosuppressants was considered to pose a high risk. After obtaining informed consent, remission induction therapy was initiated with mepolizumab (MPZ; 300 mg/M) in combination with high-dose corticosteroid therapy (equivalent to 70 mg/day of prednisolone). After treatment initiation, eosinophil counts and inflammatory responses decreased. Moreover, the abdominal pain and purpura resolved, and renal/hepatic dysfunction and peripheral neuropathy also improved. While the corticosteroid dose was subsequently reduced, no relapse was observed. Approximately 2 years later, the corticosteroid was discontinued. After the discontinuation of the corticosteroid, the patient continued treatment with MPZ alone and has remained in remission for approximately 6 months. Therefore, MPZ may be useful as a remission induction therapy in ANCA-negative EGPA resistant to steroids.

Antimycobacterial and anti-inflammatory activities of thiourea derivatives focusing on treatment approaches for severe pulmonary tuberculosis

Tuberculosis (TB) remains a serious public health problem and one of the main concern is the emergence of multidrug-resistant and extensively resistant TB. Hyper-reactive patients develop inflammatory necrotic lung lesions that aggravate the pathology and facilitate transmission of mycobacteria. Treatment of severe TB is a major clinical challenge that has few effective solutions and patients face a poor prognosis, years of treatment and different adverse drug reactions. In this work, fifteen novel and thirty-one unusual thiourea derivatives were synthesized and evaluated in vitro for their antimycobacterial and anti-inflammatory potential and, in silico for ADMET parameters and for structure–activity relationship (SAR). Thioureas derivatives 10, 15, 16, 28 and 29 that had shown low cytotoxicity and high activities were selected for further investigation, after SAR study. These five thioureas derivatives inhibited Mtb H37Rv growth in bacterial culture and in infected macrophages, highlighting thiourea derivative 28 (MIC50 2.0 ± 1.1 and 2.3 ± 1.1 µM, respectively). Moreover, these compounds were active against the hypervirulent clinical Mtb strain M299, in bacterial culture, especially 16, 28 and 29, and in extracellular clumps, highlighting 29, with MIC50 5.6 ± 1.2 µM. Regarding inflammation, they inhibited NO through the suppression of iNOS expression, and also inhibited the production of TNF-α and IL-1β. In silico studies were carried out suggesting that these five compounds could be administered by oral route and have low toxicological effects when compared to rifampicin. In conclusion, our data show that, at least, thiourea derivatives 16, 28 and 29 are promising antimycobacterial and anti-inflammatory agents, and candidates for further prospective studies aiming new anti-TB drugs, that can be used on a dual approach for the treatment of severe TB cases associated with exacerbated inflammation.

Severity of inflammatory lung lesions in COVID-19 based on computed tomography examination as a prognostic factor for respiratory failure and death.

Severity of inflammatory lung lesions in COVID-19 based on computed tomography examination as a prognostic factor for respiratory failure and death.

P2x7 Receptor Signaling Blockade Reduces Lung Inflammation and Necrosis During Severe Experimental Tuberculosis.

The risk of developing severe forms of tuberculosis has increased by the acquired immunodeficiency syndrome (AIDS) epidemic, lack of effective drugs to eliminate latent infection and the emergence of drug-resistant mycobacterial strains. Excessive inflammatory response and tissue damage associated with severe tuberculosis contribute to poor outcome of the disease. Our previous studies using mice deficient in the ATP-gated ionotropic P2X7 receptor suggested this molecule as a promising target for host-directed therapy in severe pulmonary tuberculosis. In this study, we assessed the effects of P2X7 pharmacological blockade on disease severity. First, we observed an increase in P2RX7 gene expression in the peripheral blood of tuberculosis patients compared to healthy donors. Lung leukocytes of mice infected with hypervirulent mycobacteria also showed increased expression of the P2X7 receptor. P2X7 blockade in mice with advanced tuberculosis recapitulated in many aspects the disease in P2X7-deficient mice. P2X7-directed therapy reduced body weight loss and the development of inflammatory and necrotic lung lesions, as well as delayed mycobacterial growth. Lower TNF-α production by lung cells and a substantial reduction in the lung GR-1+ myeloid cell population were observed after P2X7 inhibition. The effector CD4+ T cell population also decreased, but IFN-γ production by lung cells increased. The presence of a large population with characteristics of myeloid dendritic cells, as well as the increase in IL-6 production by lung cells, also indicate a qualitative improvement in the pulmonary immune response due to P2X7 inhibition. These findings support the use of drugs that target the P2X7 receptor as a therapeutic strategy to improve the outcome of pulmonary tuberculosis.

Impact of [18F]FDG-PET and [18F]FLT-PET-Parameters in Patients with Suspected Relapse of Irradiated Lung Cancer.

Radiation-induced changes may cause a non-malignant high 2-deoxy-2-[18F]fluoro-d-glucose (FDG)-uptake. The 3′-deoxy-3′-[18F]fluorothymidine (FLT)-PET/CT performs better in the differential diagnosis of inflammatory changes and lung lesions with a higher specificity than FDG-PET/CT. We investigated the association between post-radiotherapy FDG-PET-parameters, FLT-PET-parameters, and outcome. Sixty-one patients suspected for having a relapse after definitive radiotherapy for lung cancer were included. All the patients had FDG-PET/CT and FLT-PET/CT. FDG-PET- and FLT-PET-parameters were collected from within the irradiated high-dose volume (HDV) and from recurrent pulmonary lesions. For associations between PET-parameters and relapse status, respectively, the overall survival was analyzed. Thirty patients had a relapse, of these, 16 patients had a relapse within the HDV. FDG-SUVmax and FLT-SUVmax were higher in relapsed HDVs compared with non-relapsed HDVs (median FDG-SUVmax: 12.8 vs. 4.2; p < 0.001; median FLT-SUVmax 3.9 vs. 2.2; p < 0.001). A relapse within HDV had higher FDG-SUVpeak (median FDG-SUVpeak: 7.1 vs. 3.5; p = 0.014) and was larger (median metabolic tumor volume (MTV50%): 2.5 vs. 0.7; 0.014) than the relapsed lesions outside of HDV. The proliferative tumor volume (PTV50%) was prognostic for the overall survival (hazard ratio: 1.07 pr cm3 [1.01–1.13]; p = 0.014) in the univariate analysis, but not in the multivariate analysis. FDG-SUVmax and FLT-SUVmax may be helpful tools for differentiating the relapse from radiation-induced changes, however, they should not be used definitively for relapse detection.

The integrated stress response mediates necrosis in murine Mycobacterium tuberculosis granulomas.

The mechanism by which only some individuals infected with Mycobacterium tuberculosis develop necrotic granulomas with progressive disease while others form controlled granulomas that contain the infection remains poorly defined. Mice carrying the sst1-suscepible (sst1S) genotype develop necrotic inflammatory lung lesions, similar to human tuberculosis (TB) granulomas, which are linked to macrophage dysfunction, while their congenic counterpart (B6) mice do not. In this study we report that (a) sst1S macrophages developed aberrant, biphasic responses to TNF characterized by superinduction of stress and type I interferon pathways after prolonged TNF stimulation; (b) the late-stage TNF response was driven via a JNK/IFN-β/protein kinase R (PKR) circuit; and (c) induced the integrated stress response (ISR) via PKR-mediated eIF2α phosphorylation and the subsequent hyperinduction of ATF3 and ISR-target genes Chac1, Trib3, and Ddit4. The administration of ISRIB, a small-molecule inhibitor of the ISR, blocked the development of necrosis in lung granulomas of M. tuberculosis-infected sst1S mice and concomitantly reduced the bacterial burden. Hence, induction of the ISR and the locked-in state of escalating stress driven by the type I IFN pathway in sst1S macrophages play a causal role in the development of necrosis in TB granulomas. Interruption of the aberrant stress response with inhibitors such as ISRIB may offer novel host-directed therapy strategies.